Major depressive disorder (MDD) is a worldwide public health problem, responsible for considerable disability, mortality, cost, and medical comorbidity. Psychosocial stressors have been linked with the onset, severity, and course of MDD and depressive symptoms. According to the stress-sensitization or kindling model of depression, the stress and depression association is dynamic, with more significant stressors triggering initial depressive episodes, and less significant stressors capable of triggering subsequent depressive episodes. While several pathophysiological mechanisms of stress sensitization have been proposed, including alterations in immune ("the cytokine model of depression") and hormonal responses to psychological stressors, it is possible that endocrine-immune interactions, specifically pro-inflammatory cytokine glucocorticoid resistance (GCR), underlie the stress and depression association. Thus, the purpose of this proposed study is to test a physiological explanation for the stress sensitization model of depression by examining cytokine responses to an acute psychological stressor and in vitro measures of pro-inflammatory cytokine GCR in 50 currently depressed and 50 never-depressed pre-menopausal women. The proposed study addresses whether depressed women, and particularly those with recurrent depression: 1) exhibit higher basal plasma levels of pro-inflammatory cytokines (i.e., II-1b, II-6, TNF-a), greater pro-inflammatory cytokine production in response to in vitro mitogen stimulation, and a more exaggerated pattern of pro-inflammatory cytokine responses to a Trier Social Stress Test than never-depressed controls, and 2) exhibit higher levels of basal in vitro lymphocyte pro-inflammatory cytokine GCR than never-depressed controls. This study will also address whether in vitro lymphocyte pro-inflammatory cytokine GCR is a prognostic indicator of likelihood of depression diagnosis 12 months later in depressed women. The proposed research study is designed to improve current understanding of the pathophysiology of major depressive disorder (MDD). Results of this study may lead to novel behavioral and/or pharmacological (e.g., anti-cytokine and/or anti-inflammatory agents) anti-depressant treatments for recurrent depression. Such treatments would not only benefit individuals with primary MDD, but may also extend to those with comorbid medical illnesses involving inflammatory processes (e.g., cardiovascular disease, coronary heart disease, rheumatoid arthritis, multiple sclerosis).